Date issued

Journal

Type

Language

Publisher

Links

Rights

Abstract

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 non-diabetic individuals from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycaemic traits and identify new loci. Thirty type 2 diabetes, or fasting glucose raising, alleles were associated with a measure of first phase insulin secretion at P<0.05, and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGFBP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1 and TMPRSS6 loci. The fasting glucose raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycaemic traits.

Description

Published online

Journal Article

This is the author accepted manuscript. The final version is available from American Diabetes Association via the DOI in this record.